Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the US. Recent discoveries implicate the nuclear receptor Rev-erb1 as a transcriptional link between the circadian clock and metabolism. The present proposal combines tissue-specific, genome-wide analysis of TF binding and epigenomic modifications, novel mouse genetic models, and sophisticated metabolic phenotyping to understand the physiological role of Rev-erb1 and Rev-erb2 in the coordination of circadian rhythms and metabolism. Specific Aim 1 is to determine the role of Rev-erb1 in the regulation of hepatic circadian rhythm and metabolism. The liver is a critical metabolic organ, and our preliminary data demonstrate fatty liver in mice lacking Rev-erb1. Genome-wide analysis of Rev-erb1 binding sites identifies lipid metabolic genes to which HDAC3 is recruited in a circadian manner. We hypothesize that this is a critical mechanism of circadian epigenomic control of hepatic lipid metabolism, and will test this by a combination of genome-wide approaches in informative and carefully phenotyped mouse genetic models. Specific Aim 2 is to determine the role of Rev-erb1 in adipose circadian rhythm and metabolism. Preliminary data show that mice lacking Rev-erb1 have increased white adipose tissue, and genome-wide analysis reveals binding of Rev-erb1 to a distinct set of metabolic genes. We will test the hypothesis that Rev-erb1 epigenomically controls fat- specific functions together with cooperating transcription factors. Specific Aim 3 is to determine the role of Rev- erb1 stabilization in circadian rhythm and metabolism, utilizing a novel mouse model in which Rev-erb1 is insensitive to the lithium-stimulated degradation pathway. Specific Aim 4 is to determine the role of Rev-erb2 in the regulation of circadian rhythm and metabolism. Knockdown and knockout models will test the hypothesis that Rev-erb2 has circadian and metabolic functions that are both unique and partly redundant with Rev-erb1. These integrative studies have important implications for understanding the links between circadian rhythm and metabolism that underlie the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.